Process for producing high purity 3,5-dihydroxy-6-heptenoic acid derivative

ABSTRACT

A process for producing a high purity 3,5-dihydroxy6-heptenoic acid derivative by controlling the content of impurities such as denatured substances, is provided. When a 3,5-dihydroxy-6-heptenoic acid derivative is produced by a process which comprises a step of contacting the 3,5-dihydroxy-6-heptenoic acid derivative of the formula (1) wherein R is a C 1-4  alkyl group, with a C 1-4  lower alcohol-containing solvent, an alcohol containing solvent having its content of an oxidizing substance lowered, is used to at most 0.05 molar equivalent to a 3,5-dihydroxy-6-heptenoic acid derivative, to suppress impurities contained in the 3,5-dihydroxy-6heptenoic acid derivative.

TECHNICAL FIELD

The present invention relates to a process for producing a high purity3,5-dihydroxy-6-heptenoic acid derivative having a very small content ofimpurities such as denatured substances. More particularly, it relatesto a process for producing a high purity 3,5-dihydroxy-6-heptenoic acidderivative which is useful as a medicinal intermediate such asethyl(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate(hereinafter referred to as (3R,5S) DOLE), methyl(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate(hereinafter referred to as (3R,5S) DOLM).

BACKGROUND ART

A 3,5-dihydroxy-6-heptenoic acid derivative represented by (3R,5S) DOLEor (3R,5S) DOLM is known to be useful as an intermediate for ahyperlipemia preventive or curative medicine, or for a medicine forlowering cholesterol (HMG-CoA reductase inhibitor) (JP-A-1-279866,EP-A-304063, U.S. Pat. No. 5,011,930). Such a 3,5-dihydroxy-6-heptenoicacid derivative is produced as a racemic modification as it has anasymmetric carbon. It is known that an optically active isomer can beproduced by optical resolution of the racemic modification by liquidchromatography employing an optical isomer separation HPLC column.(WO95/23125)

DISCLOSURE OF THE INVENTION

In optical resolution of a 3,5-dihydroxy-6-heptenoic acid derivativesuch as (3R,5S) DOLE or a (3R,5S) DOLM by means of an optical isomerseparation column (such as CHIRALCEL OF), as an eluent, analcohol-containing solvent, for example, a mixed solvent of an alcoholwith a hydrocarbon (for example, a mixed solvent ofn-hexane/isopropanol) is usually used. A fraction of the3,5-dihydroxy-6-heptenoic acid derivative eluted in such a solvent iscollected, and the solvent is distilled off. The obtained alcoholsolution of the 3,5-dihydroxy-6-heptenoic acid derivative is furthersubjected to solvent exchange with a solvent for recrystallization suchas a hydrocarbon or a hydrocarbon partially containing an alcohol,followed by crystallization, whereby a pure 3,5-dihydroxy-6-heptenoicacid derivative is obtainable as crystals.

However, with the 3,5-dihydroxy-6-heptenoic acid derivative produced bysuch a process, a phenomenon of formation of denatured substances maysometimes be observed during its production or storage. A3,5-dihydroxy-6-heptenoic acid derivative of the formula (1) isconverted to a base material for medicine by converting it to a calciumsalt after hydrolysis. During the process, its denatured substances tendto color a reaction solution strongly, and they will ultimately coloralso the medicinal base material. Formation of such impurities occurseven when one having a high purity made of the highest grade chemicalsis used as the mixed solvent of a hydrocarbon and an alcohol, to be usedin the production process. The content of such denatured substances isvery small with ppm order in the 3,5-dihydroxy-6-heptenoic acidderivative to be produced. However, the desired product is to be used asan intermediate for medicines, and therefore, it is necessary to lowerthe impurities as far as possible.

It is an object of the present invention to provide a novel processcapable of producing a high purity 3,5-dihydroxy-6-heptenoic acidderivative which requires no particular purification process after itsproduction, by significantly suppressing the content of the very smallamount of impurities such as denatured substances in the desired productin the case of producing a 3,5-dihydroxy-6-heptenoic acid derivativethrough liquid chromatography employing an optical isomer separationcolumn.

As a result of their extensive study to accomplish the above object, thepresent inventors have found that formation of the very small amount ofimpurities such as denatured substances in the 3,5-dihydroxy-6-heptenoicacid derivative as the desired product is caused by analcohol-containing solvent which is employed e.g. in the process ofliquid chromatography employing an optical isomer separation column.

Namely, according to the study by the present inventors, it has beenfound that, as shown in Example 1 given hereinafter, when an alcohol asthe solvent which was employed in the process for producing a3,5-dihydroxy-6-heptenoic acid derivative, was distilled andconcentrated, an oxidizing substance was found therein. And, stabilityof the 3,5-dihydroxy-6-heptenoic acid derivative as the desired productwas investigated in alcohol solvents, which contained the oxidizingsubstance in various ratios, whereby it has been found that as shownExample 2 given hereinafter, by lowering the content of the oxidizingsubstance in the alcohol-containing solvent as far as possible, theamount of denatured substances formed in the desired product can besuppressed. Particularly, it has been found that by controlling theamount of the oxidizing substance in the alcohol-containing solvent toat most 0.05 molar equivalent to the 3,5-dihydroxy-6-heptenoic acidderivative, the content of impurities in the desired product can belowered to a level of not higher than the usually allowable amount.

The present invention has been accomplished based on such a novelfinding, and is characterized by the followings:(1) A process for producing a 3,5-dihydroxy-6-heptenoic acid derivative,which comprises a step of contacting a 3,5-dihydroxy-6-heptenoic acidderivative of the formula (1):

wherein R is a C₁₋₄ alkyl group, with a C₁₋₄ lower alcohol-containingsolvent, characterized in that an alcohol-containing solvent having itscontent of an oxidizing substance lowered as far as possible, is used tosuppress the amount of impurities which are contained in the3,5-dihydroxy-6-heptenoic acid derivative.(2) The process according to above (1), wherein the step of contactingwith the alcohol-containing solvent is a step of contacting with thesolvent as an eluent for liquid chromatography employing an opticalisomer separation column for optical resolution of the3,5-dihydroxy-6-heptenoic acid derivative of the formula (1).(3) The process according to above (1) or (2), wherein the content ofthe oxidizing substance in the alcohol-containing solvent is adjusted toat most 0.05 molar equivalent to the 3,5-dihydroxy-6-heptenoic acidderivative of the formula (1).(4) The process according to above (1), (2) or (3), wherein R in theformula (1) is a methyl group or an ethyl group.(5) The process according to any one of above (1) to (4), wherein thealcohol in the alcohol-containing solvent is methanol, ethanol orisopropanol.(6) The process according to any one of above (1) to (4), wherein thealcohol in the alcohol-containing solvent having the oxidizing substanceadjusted to be at most 0.05 molar equivalent to the3,5-dihydroxy-6-heptenoic acid derivative of the formula (1), is eitherone obtained by distillation of raw material alcohol or one having rawmaterial alcohol treated with a reducing agent.

According to the present invention, formation of the very small amountof impurities such as denatured substances in the3,5-dihydroxy-6-heptenoic acid derivative as the desired product can besignificantly suppressed, and a high purity 3,5-dihydroxy-6-heptenoicacid derivative can be obtained without performing cumbersomepurification treatment for removing the very small amount of impuritiesafter its production. This is extremely meaningful in that the productis to be employed as an intermediate for medicines where even anextremely small amount of impurities may not be allowed.

The reason why the impurities in the desired material can besignificantly suppressed by the present invention, is not necessarilyclearly understood, but it may be explained as follows:

The alcohol in the alcohol-containing solvent used in the process isbasically not so stable. When the alcohol is temporally exposed to ahigh temperature, a part of it degrades into an oxidizing substance,which is considered to be included in the solvent. The oxidizingsubstance contained in the alcohol, even in a very small amount, issignificant in the step of e.g. liquid chromatography in the productionof the desired product of the present invention, in that the3,5-dihydroxy-6-heptenoic acid derivative as the desired product, willbe in contact with the alcohol-containing solvent for a long time offrom a few hours to a few days in the operation of adsorption/desorptionand during the subsequent transition period for the next treatment.

It is considered that through contact with an alcohol-containing solventfor such a long-time, a part of the desired product is oxidized by anoxidizing substance in the alcohol-containing solvent, and the oxidizedis contained as impurities in the desired product. This is supported tosome extent by the fact that denatured substances contained in thedesired product are mainly ketones formed by oxidation of hydroxylgroups of the 3,5-dihydroxy-6-heptenoic acid derivative.

BEST MODE FOR CARRYING OUT THE INVENTION

The 3,5-dihydroxy-6-heptenoic acid derivative to be produced by thepresent invention is represented by the following formula (1).

In the formula (1), R is a C₁₋₄ alkyl group, preferably a methyl groupor an ethyl group. The representative compounds are, for example,ethyl(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate ((3R,5S) DOLE), and methyl(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate ((3R,5S) DOLM). Thesesubstances are useful as intermediates for hyperlipemia preventive orcurative medicines, or for medicines for lowering cholesterol (HMG-CoAreductase inhibitor).

Such a 3,5-dihydroxy-6-heptenoic acid derivative has an asymmetriccarbon, and, a compound synthesized by a known process is a racemicmodification. In the present invention, as mentioned above, analcohol-containing solvent is employed in a process for obtaining anoptically active isomer by optical resolution of the racemicmodification by liquid chromatography employing an optical isomerseparation HPLC column (e.g. “CHIRALCEL OF” manufactured by DaicelChemical Industries, Ltd), and a contacting treatment with thealcohol-solvent is carried out.

The alcohol in the alcohol-containing solvent is usually a C₁₋₄ loweralcohol, and it may, for example, be methanol, ethanol, propanol orisopropanol. In the present invention, isopropanol is particularlyeffective. The alcohol-containing solvent may be employed as an alcoholitself depending on a case, but it is usually used as a solvent mixturewith other solvents. As an eluent in the above-mentioned liquidchromatography, a solvent mixture with a hydrocarbon is employed. Thesolvent mixture in this case is, preferably, a solvent mixturecontaining a hydrocarbon such as hexane, heptane or cyclohexane,preferably in an amount of from 500 to 50 parts by mass per 100 parts bymass of the alcohol.

In the present invention, as such an alcohol-containing solvent, onehaving the content of an oxidizing substance in the solvent lowered asfar as possible, is employed. It is particularly preferred that thecontent of the oxidizing substance in the alcohol-containing solvent isadjusted to at most 0.05 molar equivalent to the3,5-dihydroxy-6-heptenoic acid derivative. It is preferred to maintainthis amount of the oxidizing substance throughout the entire process inwhich the 3,5-dihydroxy-6-heptenoic acid derivative as the desiredproduct is in contact with the alcohol-containing solvent. In thepresent invention, the oxidizing substance contained in thealcohol-containing solvent is one obtained by an iodine titration methodaccording to the following formula. For example, it is obtained bytaking an exact amount of 20 mL of a sample (the weight is alsomeasured), diluting it with 50 mL of water, adding 2 g of potassiumiodine (KI) and 10 mL of an aqueous acetic acid solution thereto,sealing it hermetically, and then after leaving it to stand still in adark room for at least 15 min, titrating it with 0.01 mol/L of anaqueous sodium thiosulfate solution by means of a potentiometricautomatic titration method.H₂O₂+2H⁺+2I⁻→2H₂O+I₂I₂+2Na₂S₂O₃→2NaI+Na₂S₄O₆

In the present invention, if the content of the oxidizing substance inthe alcohol-containing solvent is larger than 0.05 molar equivalent tothe 3,5-dihydroxy-6-heptenoic acid derivative of the formula (1), theamount of impurities such as denatured substances included in the3,5-dihydroxy-6-heptenoic acid derivative produced cannot be reduced tosuch a low level that satisfies at most 1000 ppm which is usually deemedto be free from problem. In the present invention, the amount ofimpurities such as denatured substances in the desired product, can bedramatically reduced by bringing the content of the oxidizing substancein the alcohol-containing solvent to be preferably at most 0.05 molarequivalent, particularly preferably, at most 0.02 molar equivalent, tothe 3,5-dihydroxy-6-heptenoic acid derivative. Here, the molarequivalent of the oxidizing substance is calculated as converted tohydrogen peroxide.

As means to obtain an alcohol-containing solvent having the content ofthe oxidizing substance lowered, various methods may be employed, andsuch means are not particularly limited in the present invention.However, the following methods may preferably be employed.

One of them is a method of employing a solvent which contains an alcoholhaving a residue removed by distillation. As shown in theafter-mentioned Example 1, it is possible to certainly reduce the amountof the contained oxidizing substance by repeating distillation of theraw material alcohol. As the distillation method, a common distillationmethod such as atmospheric distillation, reduced-pressure distillationor azeotropic distillation may, for example be employed.

Another method is a method of employing a solvent which contains analcohol wherein an oxidizing substance is reduced by addition of areducing agent. As such a reducing substance, hydroquinone or sodiumthiosulfate is preferred in the present invention. When such a reducingagent is used, it is possible to suppress denaturation by lactonizationof the 3,5-dihydroxy-6-heptenoic acid derivative such as (3R,5S) DOLE or(3R,5S) DOLM, which is likely to take place when other reducing agentsare used. The reducing agent is used preferably in an amount within arange of from 0.5 to 10 equivalent, particularly preferably within arange of from 1 to 5 equivalent, to the amount of the oxidizingsubstance included in the raw material alcohol. The temperature fortreatment with the reducing agent is preferably within a range of from10 to 60° C., particularly preferably within a range of from 20 to 40°C.

Among the above two processes of obtaining an alcohol having the contentof the oxidizing substance lowered, the former process is preferred inthe present invention, because it can certainly lower the content of theoxidizing substance, and as compared with the latter process, theobtainable alcohol having the content of the oxidizing substance lowereddoes not include an excessive reducing agent or impurities such asreaction products or the reducing agent and the oxidizing substance.

A known process as disclosed in WO95/23125 or WO02/30903 may be employedfor the process of obtaining an optically active isomer by opticalresolution of the racemic modification by liquid chromatographytreatment such as a batch method or a simulated moving bed methodemploying an optical isomer separation HPLC column by using analcohol-containing solvent having the content of the oxidizing substancelowered.

The present invention will now be described in further detail withreference to Examples. However, it should be understood that the presentinvention is by no means restricted to such specific Examples.

EXAMPLE 1

A commercially available highest-grade isopropanol was concentrated 160times by distillation under atmospheric pressure to obtain aconcentrated liquid and a distillate. Distillation to concentrate theobtained distillate 160 times again, was repeated for 3 more times, 10and the amount (mgH₂O₂/g) of an oxidizing substance contained in eachisopropanol liquid obtained was measured. The results are shown inTable 1. TABLE 1 Content of the oxidizing Type of liquid substanceCommercially available isopropanol Not detected Concentrated liquidobtained by first 0.381 distillation Concentrated liquid obtained bysecond 0.114 distillation Concentrated liquid obtained by third 0.079distillation Distillate obtained by third Not detected distillation

Further, 240 mg of (3R,5S) DOLE was dissolved in 10 mL of each liquid asidentified in Table 1 and left to stand in a constant temperature bathat 40° C. for 4 days, whereby the amount of denatured substances in(3R,5S) DOLE was measured and shown in Table 2 by percentage in thetotal substances including (3R,5S) DOLE.

The impurities contained in (3R,5S) DOLE were analyzed by nuclearmagnetic resonance and mass spectrum, whereby it was confirmed that theimpurities were mainly ketones. The analysis of the content ofimpurities was carried out by using 4.6 IDx 250 mL L-ColumnODS which waspacked with octadecyl group chemically bonded type silica packing(Foundation of Chemicals Evaluation and Research Institute), anethanol/tetra/hydrofuran/0.01 M ammonium acetate solution (45:3:52,V/V/V), 1.0 mL/min, 40° C., wave length 254 nm. TABLE 2 ConcentratedConcentrated Concentrated liquid liquid liquid Distillate obtained byobtained by obtained obtained first second by third by third Timedistillation distillation distillation distillation Start 0.000% 0.000%0.000% 0.000% One day later 0.016% 0.000% 0.000% 0.000% Two days later0.031% 0.000% 0.000% 0.000% Three days later 0.049% 0.000% 0.000% 0.000%Four days later 0.076% 0.000% 0.000% 0.000%

As is evident from Table 2, the (3R,5S) DOLE that contacted for 4 dayswith the concentrated liquid obtained by the first distillation i.e. theisopropanol liquid, containing an oxidizing substance in high 5concentration, contains impurities, and their content increases withtime. On the other hand, it is evident that the (3R,5S) DOLE thatcontacted with the concentrated liquid or distillate obtained by thesecond or subsequent distillation i.e. isopropanol liquid withoutcontaining an oxidizing substance in high concentration, contains nodenatured substance even after the contact for 4 days.

EXAMPLE 2

500 mg of (3R,5S) DOLE was dissolved in 0.64 ml (equivalent to 0.5 g) ofa commercially available highest-grade isopropanol (IPA). On the otherhand, 1.0035 g of a 9.26 mmol/g H₂O₂ aqueous solution was weighed andadjusted to 10 ml with the same commercially available highest-gradeisopropanol as mentioned above, to prepare 0.929 mmol/g H₂O₂—IPA.

This H₂O₂—IPA solution was added to the above IPA solution of (3R,5S)DOLE, so that the amount of H₂O₂ in the isopropanol would be 10 μl, 20μl, 50 μl and 100 μl, respectively. The obtained liquids were left tostand for 4 days in the constant temperature bath at 40° C. under lightshielding condition, and the amounts of denatured substances (ppm)formed, were detected in the same manner as in Example 1. The resultsare shown in Table 3. The H₂O₂ content in IPA in Table 3 is the molarequivalent of H₂O₂ per (3R,5S) DOLE. TABLE 3 Amount added to the (3R,5S) DOLE solution No addition 10 μl 20 μl 50 μl 100 μl H₂O₂ Content inIPA 0 0.0084 0.017 0.042 0.084 Start 0 0 20 0 0 One day later 0 40 60140 180 Two days later 0 60 120 320 420 Three days later 0 70 170 480640 Four days later 0 110 270 830 1140

As shown in Table 3, as the peroxide concentration in isopropanolincreases, the content of impurities in (3R,5S) DOLE increases. However,it is evident that if the content of peroxide in isopropanol ismaintained to be 0.05 molar equivalent, the content of impurities in(3R,5S) DOLE can be suppressed to be at most 1000 ppm which is usuallyallowable.

EXAMPLE 3 Reducing Agent: Hydroquinone

240 mg of (3R,5S) DOLE was dissolved in 9 ml of commercially availableisopropanol. For accelerated test, to the solution, 0.5 ml (0.09 eq.) ofan isopropanol solution containing 0.097 mmol/ml of a H₂O₂ aqueoussolution was added to obtain a liquid (blank liquid), which was left tostand for 4 days in a constant temperature bath at 40° C.

On the other hand, to the above blank solution, 1 ml of a 0.0272 mmol/mlhydroquinone-isopropanol solution was further added to obtain a liquid(hydroquinone-added liquid), which was left to stand for 4 days in aconstant temperature bath at 40° C. in the same manner as above.

In the each of above tests, the amount of denatured substances containedin the obtained (3R,5S) DOLE was measured and shown in Table 4. TABLE 4Hydroquinone-added Time Blank liquid liquid Start 0.000% 0.000% One daylater 0.003% 0.002% Two days later 0.004% 0.000% Three days later 0.005%0.000% Four days later 0.007% 0.000%

EXAMPLE 4 Reducing Agent: Sodium Thiosulfate

240 mg of (3R,5S) DOLE was dissolved in 9 mL of commercially availableisopropanol. For accelerated stability test, to the solution, 0.5 ml(0.09 eq.) of an isopropanol solution containing 0.097 mmol/ml of a H₂O₂aqueous solution was added to obtain a liquid (blank liquid), which wasleft to stand for 4 days in a constant temperature bath at 40° C.(blank).

On the other hand, to the above blank solution, 1 ml of a 0.0265 mmol/mlsodium thiosulfate aqueous solution was further added to obtain a liquid(sodium thiosulfate-added liquid), which was left to stand for 4 days ina constant temperature bath at 40° C., in the same manner as describedabove.

In each of the above tests, the amount of denatured substances containedin the obtained (3R,5S) DOLE was measured and shown in Table 5. TABLE 5Blank Sodium thiosulfate-added Time liquid liquid Start 0.000% 0.000%One day later 0.003% 0.000% Two days later 0.004% 0.000% Three dayslater 0.005% 0.000% Four days later 0.007% 0.000%

1. A process for producing a 3,5-dihydroxy-6-heptenoic acid derivative,comprising contacting a 3,5-dihydroxy-6-heptenoic acid derivative of theformula (1):

wherein R is a C₁₋₄ alkyl group, with a C₁₋₄ lower alcohol-containingsolvent, wherein the alcohol-containing solvent has a content of anoxidizing substance lowered as far as possible, to suppress the amountof impurities which are contained in the 3,5-dihydroxy-6-heptenoic acidderivative.
 2. The process according to claim 1, wherein the contactingwith the alcohol-containing solvent comprises contacting with thesolvent as an eluent for liquid chromatography employing an opticalisomer separation column for optical resolution of the3,5-dihydroxy-6-heptenoic acid derivative of the formula (1).
 3. Theprocess according to claim 1, wherein the content of the oxidizingsubstance in the alcohol-containing solvent is adjusted to at most 0.05molar equivalent to the 3,5-dihydroxy-6-heptenoic acid derivative of theformula (1).
 4. The process according to claim 1, wherein R in theformula (1) is a methyl group or an ethyl group.
 5. The processaccording to claim 1, wherein the alcohol in the alcohol-containingsolvent is methanol, ethanol or isopropanol.
 6. The process according toclaim 3, wherein the alcohol in the alcohol-containing solvent with theoxidizing substance adjusted to be at most 0.05 molar equivalent to3,5-dihydroxy-6-heptenoic acid derivative of the formula (1), is eitherone obtained by distillation of raw material alcohol or one having rawmaterial alcohol treated with a reducing agent.